CN106831457A - A kind of new preparation process of the hydroxy acetophenone of 3 amino 2 - Google Patents
A kind of new preparation process of the hydroxy acetophenone of 3 amino 2 Download PDFInfo
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- CN106831457A CN106831457A CN201710110644.XA CN201710110644A CN106831457A CN 106831457 A CN106831457 A CN 106831457A CN 201710110644 A CN201710110644 A CN 201710110644A CN 106831457 A CN106831457 A CN 106831457A
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- acid
- amino
- hydroxy acetophenones
- dichloromethane
- chloroform
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of new preparation process for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2, have main steps that with the sulfonic acid of 2 amino-phenol 4 be initiation material, through acylation, Fries resets, and hydrolysis, deprotection is obtained.Compared with prior art, the present invention it is raw materials used it is cheap be easy to get, technique easily realizes industrialization, and gained final products purity is high；Without dangerous technique, equipment is simple；Route is novel, and synthetic route is short.
Description
Technical field
The present invention relates to field of medicaments, specifically a kind of new preparation process of 3- amino -2- hydroxy acetophenones.
Background technology
Pranlukast (pranlukast, 1), chemical entitled N- [4- oxos -2- (1H-TETRAZOLE -5- bases) -4H-1- benzo pyrroles
Mutter -8- bases] -4- (4- phenylbutoxies) benzamide is the LTRA of Japanese Ono companies research and development, nineteen ninety-five
Listed in Japan first, clinic is mainly used as anti-asthma and antiallergic.To prevention and treatment Zhong Er Yan ﹑ dysmenorrhoeas and psoriasis etc.
There is good efficacy；Animal cerebral ischemia is significantly improved simultaneously, and Central nervous system adverse reaction is light.
3- amino -2- hydroxy acetophenones as Pranlukast key intermediate, its synthetic method mainly has following two：
A kind of scheme is that, with p bromophenol as raw material, through acylation, Fries resets, and nitrification, reduction is obtained.Such as：CN101450943.
Two kinds of schemes are that, with parachlorophenol as initiation material, through acylation, Fries resets, and nitrification, reduction is obtained.Such as：
BioTechnology: An Indian Journal, 8(7),987-991; 2013.Both schemes are similar to, and difference exists
It is bromo in raw materials used one, one is chloro.Synthetic schemes route is long, and reduction needs high-pressure hydrogenation, and yield is low.
Specific route is as follows：
Scheme one：
Scheme two：
The content of the invention
It is an object of the invention to provide a kind of new preparation process of 3- amino -2- hydroxy acetophenones, to solve the above-mentioned back of the body
The problem proposed in scape technology.
Synthetic route of the invention is as follows：
The present invention provides following technical scheme：
A kind of new preparation process of 3- amino -2- hydroxy acetophenones, including following synthesis steps：
The first step：With Ortho-Aminophenol -4- sulfonic acid and acetic anhydride in polar solvent, 3- acetamides are synthesized under alkali or acid catalysis
Base -4- acetyloxybenzenesulfonic acids.
Solvent selection therein, acetic acid, methyl alcohol, ethanol, pyridine, DMF, dichloromethane, chloroform etc..It is preferred that methyl alcohol, ethanol.
Alkali selection pyridine, DMAP, triethylamine, NaOH, potassium hydroxide, potassium carbonate, sodium carbonate, diisopropylethylamine etc., preferably pyrrole
Pyridine, triethylamine.The acid selection concentrated sulfuric acid, p-methyl benzenesulfonic acid, PPA etc..It is preferred that the concentrated sulfuric acid.
Second step：One pot process 3- amino -2- hydroxy acetophenones.3- acetamido -4- acetoxy acetophenones are non-
In proton solvent, Fries rearrangements, sour water solution one pot process 3- amino -2- hydroxy benzenes second are carried out through Catalyzed by Anhydrous Aluminium Chloride
Ketone.
Solvent selection chloroform therein, ethyl acetate, nitrobenzene, dichloromethane, carbon tetrachloride, carbon disulfide.It is preferred that chlorine
Imitative, dichloromethane, ethyl acetate.Acid selection dilute sulfuric acid, watery hydrochloric acid.It is preferred that watery hydrochloric acid.
Compared with prior art, the beneficial effects of the invention are as follows：（One）It is raw materials used it is cheap be easy to get, technique is easily real
Now industrialize, gained final products purity is high.（Two）Without dangerous technique, equipment is simple.（Three）Route is novel, and synthetic route is short.
Specific embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
Embodiment 1：The preparation (I) of 3- acetamido -4- acetyloxybenzenesulfonic acids
Take Ortho-Aminophenol -4- sulfonic acid (189g), acetic anhydride（224g）, methyl alcohol 400g, 10 milliliters of the concentrated sulfuric acid, back flow reaction 4h.
After reaction terminates, methyl alcohol is recovered under reduced pressure, is cooled to room temperature, adjusted to pH9- to saturated sodium bicarbonate solution is added in reaction system
10,400 milliliters of ethyl acetate extractions, are washed to neutrality, and anhydrous sodium sulfate drying, filtering is recovered under reduced pressure solvent, obtains light yellow solid
Body 264g, yield 97%.
Embodiment 2：The synthesis of 3- amino -2- hydroxy acetophenones（II）
3- acetamido -4- acetyloxybenzenesulfonic acid 136g are taken, are dissolved in 300 milliliters of chloroforms, add aluminum trichloride (anhydrous) 133g,
5h is heated to reflux, after reaction terminates, most of solvent is recovered under reduced pressure, be cooled to room temperature, under ice bath, reaction solution is slowly added into
In 30% watery hydrochloric acid, 2h is stirred at room temperature, is to slowly warm up to backflow, react 4h, after reaction terminates, reaction solution is cooled to room temperature, to
20% sodium hydroxide solution is added to adjust pH9-10 in reaction system.300 milliliters of chloroform extractions are added, neutrality is washed to, it is anhydrous
Sodium sulphate is dried, and filtering, filtrate decompression is reclaimed, residue petroleum ether：Ethyl acetate=1:The light yellow solid of 3 recrystallizations
65.7g, yield 87%.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be in other specific forms realized.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires to be limited rather than described above, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.Any reference in claim should not be considered as the claim involved by limitation.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each implementation method is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art should
Specification an as entirety, the technical scheme in each embodiment can also be formed into those skilled in the art through appropriately combined
May be appreciated other embodiment.
Claims (3)
1. a kind of novel preparation method of 3- amino -2- hydroxy acetophenones, it is characterised in that including following synthesis steps：
（1）The preparation of 3- acetamido -4- acetyloxybenzenesulfonic acids（I）：
With Ortho-Aminophenol -4- sulfonic acid and acetic anhydride as raw material, in polar solvent, 3- second is synthesized in the presence of alkali or acid
Amide groups -4- acetyloxybenzenesulfonic acids（I）, reaction equation is：
（I）
Wherein, polar solvent is acetic acid, methyl alcohol, ethanol, pyridine, DMF, dichloromethane or chloroform, and alkali is pyridine, DMAP, three second
Amine, NaOH, potassium hydroxide, potassium carbonate, sodium carbonate or diisopropylethylamine, acid are the concentrated sulfuric acid, p-methyl benzenesulfonic acid or PPA；
（2）The preparation of 3- amino -2- hydroxy acetophenones（II）
In atent solvent, under Catalyzed by Anhydrous Aluminium Chloride, there is Fries and reset in compound I, hydrolyzed through hydrochloric acid, obtain 3- ammonia
Base -2- hydroxy acetophenones, reaction equation is：
（II）
Wherein, atent solvent is chloroform, ethyl acetate, nitrobenzene, dichloromethane, carbon tetrachloride or carbon disulfide, and acid is dilute sulphur
Acid or watery hydrochloric acid.
2. the novel preparation method of 3- amino -2- hydroxy acetophenones according to claim 1, it is characterised in that step（1）In
Polar solvent be methyl alcohol or ethanol, alkali be pyridine or triethylamine, acid be the concentrated sulfuric acid.
3. the novel preparation method of 3- amino -2- hydroxy acetophenones according to claim 1, it is characterised in that step（2）In
Atent solvent be chloroform, dichloromethane or ethyl acetate, acid be watery hydrochloric acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710110644.XA CN106831457B (en) | 2017-02-28 | 2017-02-28 | A kind of preparation method of 3- amino -2- hydroxy acetophenone |
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| CN201710110644.XA CN106831457B (en) | 2017-02-28 | 2017-02-28 | A kind of preparation method of 3- amino -2- hydroxy acetophenone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
| KR20200082514A (en) * | 2018-12-28 | 2020-07-08 | 노승호 | Method for preparing p-Hydroxyacetophenone and cosmetic composition containing p-Hydroxyacetophenone |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0395144A (en) * | 1989-08-04 | 1991-04-19 | Ono Pharmaceut Co Ltd | Production of aminophenol derivative |
| JPH1129540A (en) * | 1997-07-04 | 1999-02-02 | Showa Kako Kk | Production of ester derivative |
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN102079688A (en) * | 2011-01-28 | 2011-06-01 | 内蒙古工业大学 | Method for preparing 2,3-dichlorotoluene |
| CN104693074A (en) * | 2013-12-06 | 2015-06-10 | 太原理工大学 | Preparation method of 2-amino-4-sulfo-6-acetaminophenol |
-
2017
- 2017-02-28 CN CN201710110644.XA patent/CN106831457B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0395144A (en) * | 1989-08-04 | 1991-04-19 | Ono Pharmaceut Co Ltd | Production of aminophenol derivative |
| JPH1129540A (en) * | 1997-07-04 | 1999-02-02 | Showa Kako Kk | Production of ester derivative |
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN102079688A (en) * | 2011-01-28 | 2011-06-01 | 内蒙古工业大学 | Method for preparing 2,3-dichlorotoluene |
| CN104693074A (en) * | 2013-12-06 | 2015-06-10 | 太原理工大学 | Preparation method of 2-amino-4-sulfo-6-acetaminophenol |
Non-Patent Citations (3)
| Title |
|---|
| 张越 等: "普仑司特合成路线图解", 《中国医药工业杂志》 * |
| 段丽君 等: "普仑司特中间体的合成工艺优化", 《高校化学工程学报》 * |
| 裴玉琼 等: "普仑司特中间体2- 乙酰胺基-6-乙酮基苯酚的合成", 《广东化工》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
| CN107098822B (en) * | 2017-06-07 | 2021-05-28 | 上海微巨实业有限公司 | Preparation method for pranlukast key intermediate 3-amino-2-hydroxyacetophenone |
| KR20200082514A (en) * | 2018-12-28 | 2020-07-08 | 노승호 | Method for preparing p-Hydroxyacetophenone and cosmetic composition containing p-Hydroxyacetophenone |
| KR102195387B1 (en) * | 2018-12-28 | 2020-12-24 | 노승호 | Method for preparing p-Hydroxyacetophenone |
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